An Efficient Procedure for the Synthesis of Morpholin-2-one-3-carboxamide Derivatives in Good Diastereoselectivity by the Ugi Reaction

Abstract

A series of 5-substituted morpholin-2-one-3-carbox­amide derivatives were efficiently synthesized by a Ugi three-­component reaction involving chiral 5,6-dihydro[1,4]oxazin-2-one substrates, isocyanides and carboxylic acids. The newly formed chiral center in the product was obtained in good diastereoselectivity.

Key words

Ugi reaction - isonitrile - multicomponent reaction - ­diastereoselectivity - morpholin-2-one

References and Notes

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7

General procedure for the synthesis of 4: To a solution of 1 were added, successively, acid 3 and isocyanide 2 under inert atmosphere. The resulting mixture was stirred at room temperature until completion (TLC), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel column to give product 4

14

4a: [a]_D ^²8 +4 (c 0.5, CHCl₃). IR (neat): 3337, 2963, 2932, 1752, 1666, 1539, 1463, 1391, 1289, 1108 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): d (two rotamers) = 7.66-7.61 (m, 4 H), 7.46-7.40 (m, 6 H), 5.98 (s, 1 H), 4.95 (s, 0.8 H), 4.82 (dd, J = 2.7, 11.5 Hz, 1 H), 4.76 (s, 0.2 H), 4.71 (dd, J = 1.3, 11.4 Hz, 0.8 H), 4.58 (m, 0.2 H), 4.47 (dd, J = 2.8, 12.0 Hz, 0.2 H), 3.93 (m, 0.8 H), 3.86 (dd, J = 4.0, 9.6 Hz, 0.2 H), 3.70 (t, J = 10.6 Hz, 0.8 H), 3.59 (dd, J = 5.3, 10.7 Hz, 0.8 H), 3.52 (t, J = 9.6 Hz, 0.2 H), 1.89 (s, 0.6 H), 1.82 (s, 2.4 H), 1.36 (s, 1.8 H), 1.33 (s, 7.2 H), 1.06 (s, 7.2 H),
1.05 (s, 1.8 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): d (two rotamers) = 169.9, 169.8, 165.7, 163.3, 162.2, 162.1, 135.4, 135.3, 132.5, 131.9, 130.2, 130.1, 127.9, 127.7, 127.6, 66.7, 65.8, 62.7, 61.0, 60.7, 60.2, 52.9, 52.6, 52.2, 50.0, 29.6, 28.3, 26.6, 21.1, 20.4, 19.0 ppm. HRMS: m/z [M + Na]⁺ calcd for C₂₈H₃₈N₂O₅Si: 533.2448; found: 533.2437.